1-(3-cyanophenyl)-3-methyl-1H-pyrazol-5-ylcarboxylic acid | 209958-58-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(3-cyanophenyl)-3-methyl-1H-pyrazol-5-ylcarboxylic acid
• 英文别名: 2-(3-cyano-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid；1-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid；1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylic acid；1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid；2-(3-cyanophenyl)-5-methylpyrazole-3-carboxylic acid
• CAS: 209958-58-7
• 化学式: C₁₂H₉N₃O₂
• 分子量: 227.222
• InChiKey: JRAJODNIRCHQMY-UHFFFAOYSA-N

物化性质

• 沸点：
  450.5±35.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  78.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(3-cyanophenyl)-3-methyl-1H-pyrazol-5-ylcarboxylic acid 在 草酰氯 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 26.0h， 生成 1-(3-cyanophenyl)-N-[2'-(tert-butylaminosulfonyl) [1,1'-biphenyl]-4-yl]-3-methyl-1H-pyrazole-5-carboxamide
  参考文献：
  名称：

  Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

  摘要：

  Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K-i = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P-1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P-4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

  DOI：

  10.1021/jm000409z
• 作为产物：
  描述：

  ethyl-1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl-carboxylate 在 LiOH 作用下， 以 四氢呋喃 为溶剂， 生成 1-(3-cyanophenyl)-3-methyl-1H-pyrazol-5-ylcarboxylic acid
  参考文献：
  名称：

  Nitrogen containing heteroaromatics as factor Xa inhibitors

  摘要：

  本申请描述了具有以下式I的含氮杂芳烃及其衍生物：##STR1##或其药用可接受的盐或前药形式，其中J为N或NH，D可以是C(.dbd.NH)NH.sub.2，这些化合物可用作因子Xa的抑制剂。

  公开号：

  US06020357A1

文献信息

• [EN] HUMAN PLASMA KALLIKREIN INHIBITORS<br/>[FR] INHIBITEURS DE LA KALLICRÉINE PLASMATIQUE HUMAINE
  申请人：BIOCRYST PHARM INC

  公开号：WO2015134998A1

  公开（公告）日：2015-09-11

  Disclosed are compounds of formula (I), as described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also provided are pharmaceutical compositions comprising at least one compound of the invention, and methods involving use of the compounds and compositions of the invention in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.

  本文披露的是公式（I）的化合物及其药用盐。这些化合物是血浆激肽酶的抑制剂。还提供了包含本发明化合物的药物组合物，以及涉及使用这些化合物和组合物治疗和预防由不需要的血浆激肽酶活性特征的疾病和症状的方法。
• [EN] NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS<br/>[FR] COMPOSES HETEROAROMATIQUES CONTENANT DE L'AZOTE, UTILISES EN TANT QU'INHIBITEURS DU FACTEUR Xa
  申请人：DU PONT PHARMACEUTICALS COMPANY

  公开号：WO1998028269A1

  公开（公告）日：1998-07-02

  (EN) The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula (I) or pharmaceutically acceptable salt or prodrug forms thereof, wherein J is N or NH and D may be C(=NH)NH2, which are useful as inhibitors of factor Xa.(FR) La présente invention se rapporte à des composés hétéroaromatiques contenant de l'azote et à des dérivés de tels composés représentés par la formule (I), ou à des sels ou bioprécurseurs pharmaceutiquement acceptables de ces composés utiles en tant qu'inhibiteurs du facteur Xa. Dans la formule (I), J est N ou NH et D peut être C(=NH)NH2.

  (中) 本申请描述了含氮杂环芳香族化合物及其衍生物的公式(I)，或其药学上可接受的盐或前药形式，其中J为N或NH，D可能是C(=NH)NH2，这些化合物可用作凝血因子Xa的抑制剂。
• Substituted dihydro 3-halo-1h-pyrazole-5-carboxylates their preparation and use
  申请人：——

  公开号：US20040198987A1

  公开（公告）日：2004-10-07

  This invention relates to a compound of Formula I, a method for its preparation and its use in the preparation of a compound of Formula II wherein R 1 , R 2 , R 3 , X and n are as defined in the disclosure. This invention also discloses preparation of compounds of Formula III wherein R 1 , R 2 , R 6 , R 7 , R 8 and n are as defined in the disclosure. Also disclosed are certain intermediates of Formula 4 for the preparation of compounds of Formula I wherein X is N and R 2 , R 3 and n are as defined in the disclosure. 1

  本发明涉及一种I式化合物，其制备方法及其在制备II式化合物中的应用，其中R1、R2、R3、X和n如本公开说明书所定义。本发明还揭示了制备III式化合物的方法，其中R1、R2、R6、R7、R8和n如本公开说明书所定义。还揭示了某些4式中间体，用于制备I式化合物，其中X为N，R2、R3和n如本公开说明书所定义。
• Novel substituted 1H-dihydropyrazoles, their preparation and use
  申请人：Annis David Gary

  公开号：US20060128965A1

  公开（公告）日：2006-06-15

  This invention provides compounds of Formula I, methods for their preparation and use for preparing compounds of Formula II wherein R 1 , R 2 , R 3 , R 5 , R 6 , X and n are as defined in the disclosure. This invention also discloses preparation of compounds of Formula III wherein R 1 , R 2 , R 7 , R 8 , R 9 and n are as defined in the disclosure. This invention also pertains to certain compounds of Formula 4 and 6 used to prepare compounds of Formula I. wherein R 1 , R 2 , R 5 , X and n are as defined in the disclosure.

  本发明提供了公式I的化合物，其制备方法以及用于制备公式II的化合物，其中R1、R2、R3、R5、R6、X和n如披露所定义。本发明还揭示了公式III的化合物的制备方法，其中R1、R2、R7、R8、R9和n如披露所定义。本发明还涉及用于制备公式I的某些公式4和6的化合物，其中R1、R2、R5、X和n如披露所定义。
• Novel substituted 1h-dihydropyrazoles, their preparation and use
  申请人：——

  公开号：US20040171649A1

  公开（公告）日：2004-09-02

  1 This invention provides compounds of Formula (I), methods for their preparation and use for preparing compounds of Formula (II) wherein R 1 , R 2 , R 3 , R 5 , R 6 , X and n are as defined in the disclosure. This invention also discloses preparation of compounds of Formula (III) wherein R 1 , R 2 , R 7 , R 8 , R 9 and n are as defined in the disclosure. This invention also pertains to compounds of Formula 4 and 6 used to prepare compounds of Formula (I), wherein R 1 , R 2 , R 5 , X and n are as defined in the disclosure.

  这项发明提供了公式（I）的化合物，其制备方法以及用于制备公式（II）的化合物的使用方法，其中R1，R2，R3，R5，R6，X和n如披露所定义。该发明还披露了公式（III）的化合物的制备方法，其中R1，R2，R7，R8，R9和n如披露所定义。该发明还涉及用于制备公式（I）的化合物的公式4和6，其中R1，R2，R5，X和n如披露所定义。